Breaking Immune Isolation in Glioblastoma

Glioblastoma (GBM) represents one of the prototypical immune-cold tumors, characterized by profound immune suppression, T-cell exclusion, low neoantigen burden, and a highly immunosuppressive myeloid-dominant tumor microenvironment (TME). Despite advances in immunotherapy, including immune checkpoint blockade (ICB), CAR-T cells, and cancer vaccines, clinical benefits remain limited. This review synthesizes emerging evidence on multi-modal strategies aimed at reprogramming the cold TME into an immunologically active state. We highlight innate immune agonists, oncolytic virotherapy, precision nanomedicine, metabolic modulation, and radiotherapy-immune synergies. We further propose an integrated framework combining spatial immunomics, targeted delivery technology, and TME-specific engineering to overcome the therapeutic bottlenecks of GBM. Reprogramming the cold tumor microenvironment in glioblastoma through multi-modal immunotherapeutic strategies The left panel illustrates the cold tumor microenvironment, characterized by immune suppression, exclusion of effector T cells, low neoantigen burden, and dominance of immunosuppressive myeloid cells. The central schematic summarizes four major therapeutic approaches capable of converting this immune-silent state into an immunologically active phenotype: (1) innate immune agonists (e.g., STING, TLR, RIG-I stimulation), (2) oncolytic virotherapy, (3) precision nanomedicine for targeted delivery across the blood–brain barrier, and (4) metabolic modulation to overcome hypoxia- and lactate-driven immune dysfunction. The right panel depicts the resulting immunologically active tumor microenvironment, characterized by enhanced innate immune activation, increased T-cell infiltration, and restoration of anti-tumor immune activity.